Cartilage is a complex avascular tissue that is organized into several distinct layers or zones, the superficial zone, middle zone, deep zone and a calcified cartilage zone, each of which is made up of chondrocyte cells surrounded by extra-cellular matrix. The composition of the extracellular matrix varies by zone but is composed mainly of collagens type II, IX, XI, proteoglycans and water. Although chondrocytes make up less than five percent of the volume of adult cartilage, they are responsible for producing and maintaining the extra-cellular matrix and thus proper joint function. As there is no blood supply to the cartilage matrix, cartilage has a limited ability to heal once damaged and often undergoes degenerative pathological changes. Effectively treating cartilage injuries is further complicated because a complete understanding of the mechanisms and natural history of cartilage injuries and the healing and regeneration of injured cartilage is lacking.
This lack of knowledge has both large human and economic costs because cartilage damage affects millions of people every year in the United States alone. Several hundred thousand people suffer injuries to articular cartilage in major joints, mainly due to sports injuries. It is also estimated that 50 million Americans suffer from osteoarthritis, a painful and debilitating disease that attacks the cartilage in joints.
Several attempts have been made to restore cartilage. Efforts to restore cartilage or promote cartilage repair have been largely unsuccessful for several reasons.
Current methods of surgical restoration of articular cartilage fall into three categories: (1) stimulation of fibrocartilaginous repair; (2) osteochondral grafting; and (3) autologous chondrocyte implantation. Several surgical techniques have been developed to promote the formation of fibrocartilage in areas of cartilage damage. These include subchondral drilling, abrasion, and microfracture. The concept of these procedures is that penetration of the subchondral bone allows chondroprogenitor cells from the marrow to migrate into the defect and effect repair. However, the cartilage produced by this procedure is fibrocartilage, which has relatively poor mechanical properties and does not reproduce the complex physical and chemical properties of articular cartilage.
In osteochondral grafting, articular cartilage is harvested with a layer of subchondral bone and implanted into the articular defect. Fixation of the graft to the host is accomplished through healing of the graft bone to the host bone. The major disadvantages of this technique are donor-site morbidity (in the case of autograft) and risk of disease transmission (in the case of allograft). Additionally, tissue rejection can occur with allografts which compromises the surgical result. Osteochondral allografts are also generally reserved for larger areas of damage extending deep into the subchondral bone.
Autologous chondrocyte implantation is a method of cartilage repair that uses isolated chondrocytes. Clinically, this is a two-step treatment in which a cartilage biopsy is first obtained and then, after a period of ex vivo processing, cultured chondrocytes are introduced into the defect. During the ex vivo processing, the extra-cellular matrix (ECM) is removed and the chondrocytes are cultured under conditions that promote cell division. Once a suitable number of cells are produced, they are implanted into the articular defect. Containment is provided by a patch of periosteum which is sutured to the surrounding host cartilage. The cells attach to the defect walls and produce the ECM in situ. Difficulties with restoration of articular cartilage by this technique fall into three categories: cell adherence, phenotypic transformation, and ECM production. The success of implantation of individual cells (without ECM) is critically dependent upon the cells attaching to the defect bed. Cartilage ECM has been shown to have anti-adhesive properties, which are believed to be conferred by small and large proteoglycans. In vivo studies have shown that only 8% of implanted chondrocytes remain in the defect bed after implantation in rabbits. During the process of expanding the cell population in vitro, chondrocytes usually undergo phenotypic transformation or dedifferentiation. After injection of the cells, the graft construct is incapable of bearing load and must be protected from weight bearing for several weeks to months and the overall recovery period from this form of treatment is 9-12 months.
Other attempts have been made to produce artificial cartilage which can be used to replace or repair natural cartilage. Each of the current methods of cartilage repair has substantial limitations. As a result, several laboratory approaches to production of cartilage tissue in vitro have been proposed. These generally involve seeding of cultured cells (either chondrocytes or pluripotential stem cells) into a biological or synthetic scaffold. The major drawbacks of this type of approach are: (1) difficulty in attaining or maintaining the chondrocyte phenotype; (2) unknown biological effects of the scaffold material on the implanted and native chondrocytes and other joint tissues; and (3) limited attachment of the engineered tissue construct to the defect bed. Likewise these approaches utilize a homogenous population of chondrocytes isolated generically from cartilage tissue and do not accurately imitate the layered structure or function of natural cartilage.
Accordingly, there continues to be a need for cartilage tissue which accurately mimics natural articular cartilage.